The Baltimore Huntington's Disease Project (BHDP) is a cohesive research program, which includes research on etiology, pathogenesis, and treatment. In this application, we request funding for years 11-15. Using a variety of new methods, we propose to study the mechanism of gene action in HD. Dr. Orest Hurko (Mitochondrial Function) approaches the question through Dr. Joseph Coyle (Selective Neuronal Vulnerability) uses the rodent HD model and neuronal culture to investigate the basic mechanisms leading to glutamate-induced excitotoxicity and will test drugs in these systems for their ability to prevent neuronal damage. One outcome of this work is a separately funded Experimental Therapeutic Trial of Idebenone. A related theme is the role of extra-striatal pathology in HD. Drs. Chris Ross and John Hedreen (Extra-Striatal Pathology) use neuropathological and neurochemical experiments to elucidate the pathogenetic meaning of cortical and amygdala pathology in HD. Dr. Jason Brandt (Correlates of Frontal- Striatal Degeneration) uses neuropsychological methods to assess the significance of cortical atrophy (using MRI) in cognitive and functional deficits. Dr. David Zee (Ocular Motor Function), uses novel paradigms for testing ocular motor function in HD patients to study the anatomy and function of ocular motor pathways and their changes in HD. The BHDP is coordinated through its Cores, and through the physical proximity of the investigators whose offices and laboratories are in the Meyer Building. The Administrative Core provides both formal and informal forums for discussion of ideas and progress, and provides statistical services for all Projects and Cores. The Clinical Core recruits and maintains approximately 300 well-characterized HD patients. A separately funded research project, Presymptomatic Testing for HD, grew out of the resources of the Clinical Core. The Pathology Core has brain material on over 70 HD patients, most of whom were followed until death by the Clinical Core. Progress will be reviewed by an External Review Committee. Our in-house Ethics Committee reviews questions relating to patient participation in research.